Process of alkylating organic compounds



Application filed Jul-y To all whom vii-may concern:

' Be it known that I, EUGENE Tinnitus, a citizen of the United 9" in thecounty and rotate Jersey, have inv "ed. certain new improvement inProcesses oi" Qompounds; and do i 116 following to he a lull, clear, anddescription of the invention, such as will enable others skilled in theart to which it appertains to make and use the same.

This intention relates to processes of allrylating organic compounds,more particularly compounds of the paraminophenol type; and it has to doespecially With the preparation of methyl phenacetin from phenacetin.

ill

In prior copencling applications, Serialhlos. 259,722, filed September5, 1918, and 301.58%, filed June 4: 1919, I have disclosed and claimednovel methods of alkylating compoundshaving the type formula E I (R1being an Elkylgroup and Bi an acidyl group) n Ra hy the successiveaction of an alkali metal, such as sodium, and an alkylating agent, suchas an alkyl halid. Examples of this class of compounds, to alkylation ofwhich said methods are especially applicable, are phenacetin(acetphenetidin), acetanisidm, iormyl anisidin, formyl phenetidin, etc.As stated in said prior applications, during the first stage of theallrylation as ordinarily conducted by prior methods, the mass resultingfrom the reaction of the alkali metalon the compound to be allrylatedtends to congcal even Where the reaction is conducted. n the presence ofa large amount of a suitable solvent liquid such as xylol. This is anun-- desirable condition and unfavorable for the subsequent treatmentwith an allryl 'halid, especially Where the latter is a gas like methylhromid for example. In order to have the reaction mass in the form of ahomogeneous liquid mixture for treatment with the alkylating agent,special measures are taken, in accordance with the inventions i919.Eerie! fie. $14,155".

of said prior applications, to attain this result. This can beaccomplished, for example, by ensuring the presence, in the re actionmixture resulting from the all;

treatment, of a suitable quantity of later stage product, added priorthe treatment with an alkylating' agent. it such addition he made priorto the alkali metal treatment, congelation can he entirely prevented; orif made after congclatioi has oc- 1 curred, the congealed mass isthereby liquelied without diiliculty.

In general, the objects of the present invention are similar to those ofthe inventions disclosed in said prior applications, as are also theclasses of compounds treated and the resultant products; but the desiredresults are achieved in a different and, in some respects, a distinctlymore advantageous manner, as will hereinafter appear.

According to the present process the starting material, that is, thecompound to he alkylateii, is brought into solution or homogeneousliquid mixture with. an inert solvent or vehicle, such as xylol; andthis mixture is first subjected to the action of: an agent comprising analkali metal i n avail able form, the free alkali metal itself beingsuitable, in amount materially less than is required to convert all ofsaid compound into the intermediate alkali metal derivative. Moreover,in allq lating a given quantity of the starting material, it is mostdesirable not to introduce the entire quantity into the initi almixture, but to use somewhat less, say about two-thirds, for example,with the full proportion of inert solvent or vehicle, the rest. of thestarting material and of the al lrali metal being added at a laterstage, as will heexplained hereinatter. By proceeding' in this manner.tendencyoi? the intermediate derivative to separate out may he overcomeand a homogeneous liquid reaction mixture continuously maintained. Whilethe proportion of alkali metal initially used may vary somewhat. only somuch should be used as Will yield a noncongealing mixture of saidcompound with the intermediate derivative and the inert menstruum orvehicle. The resultant liquid mass is then subjected to the action ofthe desired alkylating agent to convert the intermediate derivativeintothe desired alkylated compound, which remains after formation in liquidmixture with unchanged well as of that added at this stage.

starting compound and inert menstruum.

At this stage there is added more of thestarting material, specificallythe remainder 0 the aforesaidgiven quantity thereof, and also a furtheramount of alkali metal sufiicient to ensure conversion into the alkalimetal derivative of any unaltered portion of the starting materialinitially usedi as onversion of the resultant intermediate compound intothe desired alkylated compound can be effected with the aid of a furtherquantity of the alkylating agent.

very slowly, making it ordinarily desirable to use somewhat less thanthe theoretical proportion in order to ensure complete solution. Thisprecaution is rendered unnecessary by the present invention, with thefurther result that there need be practically no unchan ed starting comound to separate from the esired alkylate product. -The whole procedureis thus simplified, expedited, and rendered smoother.

In order to afford a fuller understanding of the underlying principlesof the invention,

' a particularly desirable embodiment thereof as applied to themanufacture of methyl henacetin from phenacetin will be described indetail by way of an illustrative example.

S ecific quantities of the materials em-- oyed will be mentioned, but itwill be unerstood that these may be varied not only in absolute amountbut also in proportions, although the pro ortions hereinafter specifiedare those w ich at present are considered best. 1

In a typical procedure within the invention, where it is desired toconvert say 117 pounds of phenacetin into methyl phenacetin, only 80pounds of phenacetin are initially mixed with 100 pounds of warm xylolto give a homogeneous liquid mass. These proportions give a mixture ofsuch density that metallic sodium will float upon it, which is highlydesirable. The amount of xylol used is therefore always best limitedaccordingly. To the warm mixture or solution, contained in a suitablereaction vessel, is added metallic sodium in amount equal in thisspecific example to about one-half that theoretically necessary forcombination with all of the phenacetin present. An addition of about, 5pounds of S dium at Furthermore,

Lamas this stage in the present example is good practice. The reactionproceeds vigorously with eneration of considerable heat and evolution ofhydrogen, the sodium floating on the mixture until completely dissolved,so that the end of the reaction is readily observed. Some of the xyloldistils ofi and may be recovered with the aid of a condenser. The massresultin from the reaction is a homogeneous liquid which exhibits notendency toward crystallization and is in pounds of methyl bromid,whereas theory requires but 20.65 pounds. It is found that the use ofthe small excess of meth l bromid which the reaction mixture will takeup at this stage, about 5 per cent in this instance, has a desirableefiect in the remaining stages of the process, particularly infacilitating and expediting complete solution of the second portion ofmetallic sodium which is now added, after adding the remaining 37 poundsof phenacetin, without its being necessary first to separate the sodiumbromid present in the reaction mixture as a result 0 In the presentspecific example, this second portion of sodium amounts to ten pounds.As before, the reaction proceeds ex editiously and smoothly tocompletion, t e sodium floating until it has all gone into solution,and. moderate external heating being resorted to toward the last ifnecessary, but the heat of the reaction itself ordinarily suflicing tocarry it through. The reaction mass shows no tendency to solidify orcrys' tallize, remaining perfectly liquid throughout. Xylol is bestadded in suflicient quantity to make up the loss by distillation, asbefore, and methyl bromid gas is again led into the mass until no longertaken up there;- by. A volume of gas equivalent to 40.75 pounds ofmethyl bromid is sufiicient in this instance. The entire amount ofphenacetin originally present in the starting batch has now beenconverted into methyl phenacetin. The xylol solution of methylphenacetin is next decanted from the accompanying so-. dium bromid whichsettles out rapidly under phenacetin by distillation at ordinary presthetreatment with methyl bromid.

i the described conditions of operation, the

sure, the distillation being materially exthe scope of the invention asdefined in theappended claims.

claim:

1. The process of alkylating'acylamine organic compounds capable ofalkylation by the action of alkali metal and an alkylating agent, whichcomprises subjecting an acylamine organic compound in liquid conditionto the successive action of an alkali metal in available form and analkylating agent, in quantit insufiicient to bring about congelation oft e reaction mass or to effect complete alkylation, and thenefiectingmore complete alkylation by further treatment with alkali metal andalkylating agent. 2. The process of alkylating organic compounds havingthe type formula (B being an alkyl group and R: an acidyl group) larlyequivalent to said compound to avoid congelation of the reactionmixture, treat ing the resultant intermediate product in liquidcondition with an alkyl halid, and then repeating the treatment withalkali metal and alkyl halid to effect further alkylation.

3. The processvof preparing methyl phenacetin which comprises subjectinga liquid mixture of phenacetin and a diluent vehicle to tire action ofan alkali metal in available form and in amount sufiiciently less thanthat molecularly equivalent to the phenacetin to avoid congelation ofthe reaction mixture, subjecting the resultant mixture to the action ofan alkyl halid, and then effecting further alkylation bysuccessivetreatment with more alkali metal and alkyl halid;

4. The process of preparing methyl phe-' nacetin which comprisessubjecting a liquid mixture of phenacetin and xylol to the action ofabout one-half the amount of metallie sodium molecularly equivalent tothe phenacetin, passing methyl bromid into the resultant liquid mass,adding to the mass more phenacetin and a further amount of metallicsodium sufiicient to react with substantially all the phenacetin presentin the mixture, completing the methylation with methyl bromid, andobtaining methyl phenacetin from the mixture finally obtained.

5. The process of preparing methyl phenacetin which compr1ses subjectinga liquid mixtu re of phenacetinand a diluent vehicle to the action of analkali metal in amount sufliciently less than that molecularlyequivalent to the phenacetin to avoid congelation of the reactionmixture, subjecting the resultant mixture to the action of an ,r alkylhalid in excess of that theoretically required for complete reactionwith all the intermediate alkali compound of phenacetin present, andthen efiecting further alkylation by successive treatment with morealkali metal and alkyl halid.

6.. The process of preparing methyl phenacetin which comprisessubjecting a liquid mixture of phenacetin and xylolto the action ofabout one-half the amount of metal- ,lic sodium! molecularly equivalentto the phenacetin, passing an excess of 'methyl bromid into theresultant liquid mass, adding to the mass more phenacetin and a furtheramount of metallic sodium. suflicientto react with substantially all thephenacetin present in the mixture, completing the -.methylation withmethyl bromid, and I I obtaining methyl phenacetin from the mixturefinally obtained.

7. The process of preparing methyl phe-.

nacetin which comprlses mixing with an inert liquid vehicle a quantityofphenacetin less than a given amount which is to be methylated butsuflicient to give a liquid mixture dense enough to float metallicsodium, subjecting the mixture to the action of -metallic sodium inquantity less than is molecularly. equivalent to the phenacetin present,treating the resultant mass with a methylating agent, adding theremainder of said given amount of phenacetin, repeating the successivetreatments with metallic sodium and methylating agent, andseparatingmethyl phenacetin from the reaction mixture.

' In testimony whereof I hereunto afix my signature. 7

EUGENE THEIMER.

